1. Field of the Invention
The invention is directed to purified and isolated IL-1 receptor family members. In particular the present invention relates of DNA encoding IL-1 Receptor Accessory Protein splice variant polypeptides, polypeptides encoded by the DNA, antibodies generated against these polypeptides, fragmented peptides derived from these polypeptides, and uses thereof.
2. Description of Related Art
Interleukin-1 (IL-1) is a member of a large group of cytokines whose primary function is to mediate immune and inflammatory responses. There are several members of the IL-1 ligand family, including IL-1 alpha (IL-1α), IL-1 beta (IL-1β), IL-1 eta, IL-1 receptor antagonist (IL-1ra), IL-1 delta (IL-1δ), and IL-18 (previously known as IGIF and sometimes IL-1 gamma), 1L-1 epsilon (IL-1ε), and IL-1 zeta (IL-1ζ). IL-1 that is secreted by macrophages is actually a mixture of mostly IL-1β and some IL-1α (Abbas et al., 1994). IL-1β and IL-1α are the products of two different genes located on chromosome 2. IL-1β and IL-1α are synthesized as precursors without leader sequences and require specific cellular proteases to process to their mature forms. Although the two forms are less than 30 percent homologous to each other, they both bind to the same receptors and have similar activities.
IL-1ra is a biologically inactive form of IL-1 that is structurally homologous to IL-1 and binds to the same receptors. In contrast to IL-1β and IL-1α IL-1ra is produced with a signal sequence which allows for efficient secretion into the extracellular region where it competitively competes with IL-1 for binding IL-1 receptors. (Abbas et al., 1994).
The actions of IL-1 are mediated through interaction with the type I IL-1 receptor. IL-1 binding to the type I receptor allows the IL-1/IL-1 receptor binding complex to interact with a another protein of similar structure, called IL-1 receptor accessory proteins (IL-1 AcP), to form a ternary complex. The ternary complex initiates a signaling response that includes the association of the cytoplasmic domains of the IL-1 receptor and IL-1R AcP with MyD88, IRAK-1, IRAK-2, IRAK-M, and TRAF6.
The biological functions of IL-1 include activating vascular endothelial cells and lymphocytes, local tissue destruction, and fever (Janeway et al., 1996). At low levels, IL-1 stimulates macrophages and vascular endothelial cells to produce IL-6, upregulates molecules on the surface of vascular endothelial cells to increase leukocyte adhesion, and indirectly activates inflammatory leukocytes by stimulating mononuclear phagocytes and other cells to produce certain chemokines that activate inflammatory leukocytes. Additionally, IL-1 is involved in other inflammatory responses such as induction of prostaglandins, nitric oxide synthetase, and metalloproteinases. These IL-1 functions are crucial during low level microbial infections. However, if the microbial infection escalates, IL-1 acts systemically by inducing fever, stimulating mononuclear phagocytes to produce IL-1 and IL-6, increasing the production of serum proteins from hepatocytes, and activating the coagulation system. IL-1 has been implicated in chronic inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. There is increasing evidence that IL-1 plays a role in osteoporosis. All of these activities are initiated by the signaling function of the cytoplasmic portion of the type I IL-1R and the IL-1RAcP. Given the important function of IL-1 and IL-1R, there is a need in the art for additional cytokine receptors similar to the IL-1R family. Despite the growing body of knowledge, there is still a need in the art for the identity and function of proteins involved in cellular and immune responses.